The invention relates to the synthesis of xcex2-keto esters. More particularly, the invention relates to a highly chemo- and stereoselective synthesis of xcex2-keto esters via a polymer-supported lipase catalyzed transesterfication.
xcex2-keto esters are noteworthy in that they represent an important class of organic building blocks used in the synthesis of complex natural products (S. Benetti, et al., Chem Rev. 1995, 95, 1065). A seemingly straight-forward method to prepare these molecules is through an alcohol based transesterification (J. G. Gilbert, et al., J. Org. Chem. 1988, 53, 449; D. F. Taber, et al., J. Org. Chem. 1985, 50, 3618). Yet the synthesis of allylic and propargylic xcex2-keto esters is not trivial by this route due to their acid/base lability and sigmatropic rearrangement of the xcex2-keto ester. To circumvent these problems a report has appeared describing the heating of alcohols with xcex2-keto esters in toluene (C. Mottet, et al., J. Org. Chem. 1999, 64, 138;). However, the reaction times were lengthy and yields variable for many of the substrates. Another mild method uses crystalline microporous nanosilicates (zeolites) as the catalyst for the transesterification in refluxing toluene to avoid potential side reactions, but here the yields were even lower compared to the former case (B. S. Balaji, et al., J. Chem. Soc. Chem. Commun. 1996, 707). Furthermore, none of these or any of the conventional methods display stereoselectivity or chemoselectivity between aliphatic alcohols or phenols. What is required is a general method of synthesizing xcex2-ketoesters either as racemates or as single enantiomers. What is required is a general method for resolving alcohol racemates.
Candida antarctica lipase B (CALB) immobilized on a macroporous poly(propylene) resin (Novozym 435) catalyzed the transesterification of xcex2-keto esters under environmentally safe conditions. The reactions were performed by simply solubilizing the alcohols in methyl or ethyl xcex2-keto esters and then treating the reaction mixture with the lipase under reduced pressure. The xcex2-keto ester products were obtained in high yields ( greater than 90%) and CALB was chemoselective in the acylation of aliphatic alcohols in the presence of phenols. In addition, CALB was able to resolve sec-alcohols with high enantioselectivity. This is a general route to prepare xcex2-keto esters by lipase-catalyzed transesterification and it can be of ample use due to its mild, solvent-free conditions. Moreover, it also provides a simple protocol to produce optically active xcex2-keto esters that are useful building blocks and starting materials for natural product synthesis.
One aspect of the invention is directed to a process for synthesizing chiral xcex2-keto ester products by way of a lipase catalyzed transesterification. In the first step of the process, an acyl donor xcex2-keto ester, a racemic alcohol, and a catalytic concentration of a lipase are admixed under catalytic contitions. In the second step of this aspect of the invention, a transesterification of the acyl donor xcex2-keto ester with the racemic alcohol is catalyzed by means of the lipase for producing the chiral xcex2-keto ester product. Preferred racemic alcohols include allylic, propargylic, benzylic, allenic, and aliphatic alcohols. A preferred lipase is Candida antartica lipase B (CALB). Preferred acyl donor xcex2-keto esters include a methyl ester or an ethyl ester. A preferred solvent is the acyl donor xcex2-keto ester.
Another aspect of the invention is directed to a process for resolving a racemic alcohol. In the first step of the process the racemic alcohol is admixed with a catalytic concentration of a lipase in the presence of an excess of acyl donor xcex2-keto ester under catalytic contitions. In the second step of the process, a transesterification of the acyl donor xcex2-keto ester with the racemic alcohol is catalyzed by means of lipase for resolving the racemic alcohol. producing the chiral xcex2-keto ester product. Preferred racemic alcohols include allylic, propargylic, benzylic, allenic, and aliphatic alcohols. A preferred lipase is Candida antartica lipase B (CALB). Preferred acyl donor xcex2-keto esters include a methyl ester or an ethyl ester. A preferred solvent is the acyl donor xcex2-keto ester.